The 1-carba(1-dethia)-3-cephem-4-carboxylic acids, hereinafter 1-carbacephalosporins, or carbacephs, possess the 4,6-bicyclic ring system represented by the following structural formula ##STR2## wherein the arbitrary numbering system employed according to the cepham nomenclature is used for convenience as indicated.
1-Carbacephalosporin compounds provide significant synthetic challenges. The 1-carbacephalosporins thus far have not been obtained from natural sources, for example, as microbial metabolites. Accordingly, methods for the total synthesis of these promising compounds are highly desirable, particularly methods which are adaptable to large scale manufacture. One of the more noteworthy approaches to total synthesis of 1-carbacephalosporins is the asymmetric route described by Evans, et al., U.S. Pat. No. 4,665,171.
One further route to cis-chiral azetidinones with regularly derivatized 4-allyl (and substituted allyl) groups, is provided by Blaszczak, U.S. Pat. No. 4,771,134. The Blaszczak method utilizes 4-(substituted selenyl) azetidinones as starting materials which are converted to 4-allyl(and substituted allyl) azetidinones under free radical conditions using a (2-substituted or unsubstituted allyl) tin agent.
The preparation of 1-carbacephalosporanic acids and C-3 substituted methyl derivatives thereof is taught broadly by Christensen et al., U.S. Pat. No. 4,226,866. Hirata et al., U.K. Patent Application No. 2041923 teach a process for preparing 3-halo and 3-H 1-carbacephalosporins; and Hatanaka et al., Tetrahedron Letters, Vol. 24, No. 44, pp 4837-4838 (1983), teach a process for preparing a 3-hydroxy-(+/-)-1-carbacephalosporin.